Experts Discuss Need for Development of Next-Generation DES, Insights from Pathology

MIAMI BEACH, FLA.—Currently available DES provide excellent clinical outcomes across a broad spectrum of patients; however, there remains a clinical need for development of next-generation DES, according to Stephan Windecker, MD.

“There is no doubt that newer-generation DES have advanced the field. But, issues remain,” Windecker, of the Swiss Cardiovascular Center Bern, Bern, Switzerland, said at TCT 2012.

Reasons why development is needed

Impaired durability of antirestenotic efficacy during late follow-up remains a concern, he said. One issue is neoatherosclerosis, which appears to be more prevalent with DES than BMS. In a 2011 study, neoatherosclerosis was reported in 31% of DES patients vs. 16% of BMS patients (P=.001). Clinical evidence from trials such as ABSORB Cohort B and ISAR-TEST 4 have also brought to light concerns over the time courses during which late luminal loss and target lesion revascularization occur.

Windecker also discussed device- vs. patient-oriented outcomes. Nonculprit lesions remain important, he said, as they may account for more than half of coronary events after successful PCI. Prospective data demonstrate nonculprit lesions are responsible for events particularly if combined with reduced minimal lumen area and increased plaque burden. “This puts forward the question of whether we may be able, in the future, to perform plaque sealing for certain devices. Identification and treatment of these lesions requires careful study,” he said.

Also important to the need for clinical development is the consideration of patients with diabetes, he said. Available new-generation DES are unable to improve outcomes in diabetic patients beyond results obtained with paclitaxel-eluting stents (PES; Taxus, Boston Scientific), and further improvement is needed, according to Windecker. Analysis of the SPIRIT II, III, IV and COMPARE trials revealed that nondiabetic patients experienced lower rates of TLR (3.6% vs. 6.9%; P<.0001) and definite or probable stent thrombosis (0.3% vs. 2.4%; P<.0001) with newer-generation DES as compared with PES. Conversely, in diabetic patients, the same improvements in safety and efficacy were not observed (TLR: PES, 6.1% vs. everolimus-eluting stent (EES), 5.5%; P=.60; stent thrombosis: PES, 2% vs. EES, 1.6%; P=.50).

Prolonged dual antiplatelet therapy (DAPT) after DES implantation was identified as another area of potential improvement with next-generation DES. Accumulating evidence, including from the PRODIGY trial, show that shorter duration of DAPT (6 months) provides comparable protection from ischemic outcomes to a 24-month regimen (P=.91). In addition, 6-month DAPT duration was associated with lower risks for type II, III or V BARC bleeding compared with 2 years’ duration (P=.00018). Stent thrombosis remains an issue, as even with newer-generation stents, DAPT use for 6 months is associated with a higher risk for stent thrombosis than dual therapy use beyond 6 months. “The ideal DES would not require any DAPT,” Windecker said.

Pathology insights from human specimens

In another presentation, Renu Virmani, MD, of CVPath Institute, Gaithersburg, Md., discussed data on 412 DES lesions from 269 patients in the CVPath Autopsy Registry.

“Uncovered strut is the primary substrate responsible for late and very late stent thrombosis following first-generation DES placement where penetration of the nectrotic core, bifurcation stenting, hypersensitivity (sirolimus-eluting stents [SES]) and malapposition (PES and SES) are associated with delayed healing,” Virmani said.

Findings from the registry also revealed that healing of DES is observed with time and there is greater delay when DES are deployed in off-label vs. on-label usage. In off-label use, there were many more uncovered struts, she said.

Restenosis was an infrequent phenomenon in the registry and usually focal. Restenosis appears to be more frequent when there is greater injury and greater inter-strut distance.

Virmani also discussed what her team has learned from human autopsy studies of second-generation DES. Second-generation zotarlimus-eluting stents and EES show significantly less uncovered struts with lower incidence of late stent thrombosis as compared with first-generation DES, she said. Further, stent fracture is not uncommon in first-generation DES and is also observed in Xience V stents (Abbott Vascular), she said.